Activation of the aromatic hydrocarbon receptor pathway is not sufficient for transcriptional repression of BRCA-1: Requirements for metabolism of benzo[a]pyrene to 7r, 8t-dihydroxy-9t, 10-epoxy-7, 8, 9, 10 tetrahydrobenzo[a]pyrene

Brandon D. Jeffy, Donato F. Romagnolo, Brandon D. Jeffy, Ryan B. Chirnomas, Donato F. Romagnolo, Eddy J. Chen, Jean M. Gudas, Donato F. Romagnolo

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

Reduction of BRCA-1 expression through nonmutational events may be a predisposing event in the onset of sporadic breast cancer. In this study, we investigated the mechanisms through which the environmental carcinogen benzo[a]pyrene (B[a]P) lowered BRCA-1 mRNA levels in breast cancer MCF-7 cells. We report that B[a]P does not compromise the stability of BRCA-1 mRNA, but represses transcriptional activity of a 1.69-kb BRCA-1 (pGL3-BRCA-1) promoter fragment that contains both exon-1A and exon-1B transcription start sites. The loss of BRCA-1 promoter activity was accompanied by accumulation of CYP1A1 and BAX-α mRNA and p53 and p21 protein, whereas levels of Bcl-2 mRNA were reduced. The aromatic hydrocarbon receptor ligand 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD), which is not metabolized, did not affect BRCA-1 promoter activity or the cellular levels of BRCA-1 and p53 protein, but it did induce a CYP1A1-like promoter. Conversely, treatment with the B[a]P metabolite 7r, 8t-dihydroxy-9t, 10-epoxy-7, 8, 9, 10-tetrahydrobenzo[a]pyrene (BPDE) repressed BRCA-1 promoter activity and protein, while increasing p53 and p21 protein levels. Transient expression of dominant negative p53 (175 Arg→His) counteracted the detrimental effects of BPDE on BRCA-1 promoter activity and protein levels. Similarly, treatment with B[a]P, TCDD, or BPDE failed to repress transcription from the pGL3-BRCA-1 construct transfected into ZR75.1 breast cancer cells containing mutated p53 (152Pro→Leu). We conclude that activation of the aromatic hydrocarbon receptor is not sufficient for down-regulation of BRCA-1 transcription, which is, however, inhibited by the B[a]P metabolite BPDE through a p53-dependent pathway.

Original languageEnglish (US)
Pages (from-to)113-121
Number of pages9
JournalCancer Research
Volume62
Issue number1
StatePublished - Jan 1 2002

    Fingerprint

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this